Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells

Abstract

Significance Niemann-Pick type C disease (NPCD) is an incurable genetic neurological disorder. Cells with NPC mutations fail to export cholesterol from endosomal organelle to multiple other organelles. ACAT1 is an enzyme that converts cholesterol to cholesteryl esters for storage. In mutant NPC cells, cholesterol storage still occurs, although at reduced rate. Here we show that in mutant NPC cells, ACAT1 blockade (A1B) decreases cholesterol storage such that it can be utilized to fulfill cholesterol needs in multiple organelles. In mutant NPC1 mice, Acat1 gene knockout reduces pathological onset and prolongs the lifespan by 34%. This work identifies ACAT1 as a target to treat NPCD and may help to explain why A1B has been reported to ameliorate preclinical models for Alzheimer’s disease.

ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-like Receptor 4 in Microglia

“…It is known that after LPS stimulation, a portion of TLR4 is enriched at the caveolae/lipid rafts region of the PM [ 40 ]. In mouse embryonic fibroblast cells, A1B causes cholesterol translocation from the ER where ACAT1/SOAT1 resides to various membrane organelles, including the trans-Golgi network (TGN) and various other membrane organelles [ 41 ]. In the current cell system, we suspect that pre-treating cells with A1B may affect the intracellular distribution of TLR4, especially upon LPS stimulation.…”

Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity

“…The ACAT1/SOAT1 blockade has also been shown to enhance HMG-CoA reductase degradation by increasing levels of 24S-hydroxycholesterol [ 58 ] and suppress neuroinflammation by altering toll-like receptor 4 (TLR4) trafficking and activation [ 86 ]. Additionally, in a mouse model, genetic inactivation of ACAT1/SOAT1 was recently shown to benefit a rare pediatric neurodegenerative disease, Niemann-Pick type C1 (NPC1) [ 87 ]. The effects of ACAT1/SOAT1 inhibition are undoubtedly beneficial in disease contexts, but it is difficult to tie these results together with a single common thread.…”

ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-Like Receptor 4 in Microglia

“…ACATs/SOATs are potential targets to treat several human diseases, including atherosclerosis [29], certain forms of cancer {early literature reviewed in [5]}, [30], and neurodegenerative diseases that include AD [31] and NPCD [32]. There are two Acats/Soats in mammals [4].…”

“…The copyright holder for this preprint this version posted September 2, 2022. ; https://doi.org/10.1101/2022.08.30.505911 doi: bioRxiv preprint reported that in mouse embryonic fibroblast cells, A1B causes redistribution of cholesterol contents in multiple cellular compartments [32]. Thus, A1B could alter the cholesterol content of the TLR4 associated membrane microdomain at the PM and causes this domain to undergo caveolae-mediated endocytoses at a more rapid rate.…”